Author + information
- Received November 14, 2014
- Accepted December 9, 2014
- Published online February 24, 2015.
- Monica R. Shah, MD∗∗ (, )
- Nakela Cook, MD, MPH∗,
- Renee Wong, PhD∗,
- Priscilla Hsue, MD†,
- Paul Ridker, MD‡,
- Judith Currier, MD, MPH§ and
- Susan Shurin, MD‖
- ∗National Heart, Lung, and Blood Institute, Bethesda, Maryland
- †Division of Cardiology, University of California—San Francisco School of Medicine, San Francisco, California
- ‡Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard University School of Medicine, Boston, Massachusetts
- §Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California
- ‖National Cancer Institute, Bethesda, Maryland
- ↵∗Reprint requests and correspondence:
Dr. Monica R. Shah, National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Room 8173, Bethesda, Maryland 20892-7956.
The clinical challenges confronting patients with human immunodeficiency virus (HIV) have shifted from acquired immunodeficiency syndrome (AIDS)-related illnesses to chronic diseases, such as coronary artery disease, chronic lung disease, and chronic anemia. With the growing burden of HIV-related heart, lung, and blood (HLB) disease, the National Heart, Lung, and Blood Institute (NHLBI) recognizes it must stimulate and support HIV-related HLB research. Because HIV offers a natural, accelerated model of common pathological processes, such as inflammation, HIV-related HLB research may yield important breakthroughs for all patients with HLB disease. This paper summarizes the cardiovascular recommendations of an NHLBI Working Group, Advancing HIV/AIDS Research in Heart, Lung, and Blood Diseases, charged with identifying scientific priorities in HIV-related HLB disease and developing recommendations to promote multidisciplinary collaboration among HIV and HLB investigators. The working group included multidisciplinary sessions, as well as HLB breakout sessions for discussion of disease-specific issues, with common themes about scientific priorities and strategies to stimulate HLB research emerging in all 3 groups.
- acquired immunodeficiency syndrome
- cardiovascular disease
- coronary artery disease
- disease progression
- risk factors
Tremendous progress in the treatment of human immunodeficiency virus (HIV) has led to increased survival and a dramatic evolution of the disease (1). The clinical challenges confronting the population have now shifted from acquired immunodeficiency syndrome (AIDS)-related illnesses to chronic diseases, such as coronary artery disease, chronic obstructive lung disease, and chronic anemia (2–7). Many studies have demonstrated that the risk of developing cardiovascular (CV) disease in the HIV-positive population is significantly higher, and disease progression may be accelerated compared with in the general population (8–14). Factors that potentially contribute to the pathophysiology of HIV-related CV disease include the HIV virus itself, adverse effects of antiretroviral therapy (ART), and processes such as aging, inflammation, immune activation, microbial translocation, endothelial injury, and disordered coagulation (15–19). These unique features, along with a large burden of traditional risk factors that include cigarette smoking, hypertension, metabolic syndrome, and dyslipidemia, contribute to the increased CV risk in the HIV population (20–26).
With the growing burden of HIV-related heart, lung, and blood (HLB) disease, the National Heart, Lung, and Blood Institute (NHLBI) recognizes that it must stimulate and support research that addresses how the chronic phase of HIV affects the HLB systems. Also, because HIV offers a natural, accelerated model of common pathological processes, such as inflammation, HIV-related HLB research has the potential to yield important breakthroughs for all patients with HLB disease. Recently, the NHLBI assessed its AIDS scientific portfolio and determined that it needed to stimulate more peer-reviewed research in HIV-related HLB disease. The first step to encourage more peer-reviewed research was to identify the scientific priorities in the field to guide investigators. Although a small group of investigators has been pioneering this field for years, the NHLBI also recognized the need to develop a larger multidisciplinary scientific community to carry out research in the future. This paper and the Online Appendix summarize the CV recommendations of an NHLBI Working Group (WG), entitled Advancing HIV/AIDS Research in Heart, Lung, and Blood Diseases, which was charged with both identifying scientific priorities in HIV-related HLB disease and developing recommendations to promote multidisciplinary collaboration among HIV and HLB investigators (27).
Overview of the NHLBI WG
The WG included basic and clinical researchers with scientific expertise in HIV and HLB disease, as well as representatives from the NHLBI, the National Institutes of Health (NIH) Office of AIDS Research, the Center for Scientific Review, and other NIH institutes and centers. WG participants were asked to identify the top scientific priorities in HIV-related HLB disease, recommend research approaches to address identified critical research gaps, and develop strategies to promote collaboration and partnerships among the HIV and HLB scientific communities.
The group addressed specific HIV-related HLB diseases, as well as on cross-cutting multiorgan and multidisciplinary themes. The CV group focused on HIV-related coronary artery disease (CAD), the pulmonary group centered on HIV-related chronic obstructive pulmonary disease and pulmonary hypertension, and the hematology group addressed HIV-related anemia and the role of hematopoietic stem and progenitor cells, both as potential reservoirs and potential cures for the disease. Common themes that emerged from the conference included the role of inflammation, direct effects of organisms and medications, and barriers to multidisciplinary and cross-institutional collaboration.
The CV group focused on the specific question “Why does CAD occur at such high rates in patients with HIV?” In the following sections, we review the scientific priorities in HIV-related CV disease identified by the WG and the strategies that they proposed to advance research in the field.
During the 2-day meeting, participants were charged with refining the primary question, identifying the related scientific gaps, and developing research approaches to address the gaps. The participants were encouraged to consider basic, clinical, and population science research approaches. The preliminary recommendations were presented to the larger group, and further refined and consolidated into a final set of CV recommendations.
In addition, the WG was asked to provide recommendations on how to stimulate more HIV-related CV research to further develop this emerging field, including identifying operational challenges to multidisciplinary research, developing strategies to enhance collaboration and engage new investigators, and highlighting ways to leverage existing research resources.
The top scientific priorities focused on epidemiology, pathogenesis, and prevention and treatment. The scientific recommendations are discussed by category in the following text and listed in the Central Illustration.
The WG observed that although there is growing evidence that the incidence and prevalence of CAD in HIV patients may be higher than in noninfected people, the actual rate of CAD in the HIV-infected population, and how it compares with the noninfected population, is still not well established (28–31). Some of the limitations of previous studies included small numbers of HIV-infected patients, a deficiency of rigorously adjudicated of CV events, and inconsistent adjustment for confounding factors, such as smoking, that occur at much higher rates in the HIV population. The WG also noted that there was not enough information to fully understand the contributions to HIV-related CAD of traditional risk factors, such as hyperlipidemia, hypertension, and smoking versus the detrimental effects of the HIV virus itself, associated inflammation, ART, and coinfections (32,33).
The WG identified the following major knowledge gaps in the epidemiology of HIV-related CAD: 1) the actual incidence and prevalence of HIV-related CAD; 2) the contributions of various risk factors to the development of HIV-related CAD; 3) the long-term outcomes and determinants of outcomes following HIV-related CV events; and 4) the unique features of HIV-related CV disease in women and minorities, who are disproportionately affected by HIV. The WG suggested addressing the identified gaps by: 1) pursuing meta-analyses of current studies to fully utilize available data to estimate the incidence and prevalence of HIV-related CV disease; 2) leveraging existing HIV and CV studies to examine the epidemiology of HIV-related CAD; 3) including CV endpoints in existing HIV cohort studies and adjudicating these events—potential cohort studies included CNICS (Centers for AIDS Research Network of Integrated Clinical Systems), MACS (Multi-Center AIDS Cohort Study), the WIHS (Women’s Interagency HIV Study), and VACS (Veterans Aging Cohort Study); and 4) actively recruiting HIV-positive patients in future CV cohort studies and identifying patients with HIV who may already have been recruited in current cohorts.
The WG noted that HIV might alter and potentially accelerate the natural history of the fundamental processes underlying atherosclerosis, endothelial dysfunction, and thrombosis (34–45). The participants also observed that the mechanisms by which HIV and ART may modify these processes have still not been fully elucidated. In their discussions, the WG identified the following critical basic science research gaps: 1) the mechanisms by which HIV, inflammation, ART, coinfections, and traditional risk factors interact in HIV-related CAD; 2) the molecular pathways underlying persistent chronic inflammation in treated HIV, and the role of microbial translocation and viral reactivation, replication, and production in altering lipid function and metabolism, endothelial function, immune senescence, and thrombosis; 3) understanding whether the unique pathophysiology of HIV-related CAD offered distinct therapeutic targets; 4) the synergistic effects of smoking on the pathophysiological mechanisms contributing to HIV-related CAD, including abnormalities in coagulation and thrombosis; and 5) the characterization of the atherosclerotic plaque in HIV-related CAD through angiography and imaging.
The WG suggested the following approaches to address the identified basic science gaps: 1) develop more robust animal models to better elucidate mechanisms of HIV-related CAD; 2) conduct basic science investigations to understand how inflammation, immune dysfunction, dyslipidemia and other comorbidities, and gut microbial translocation contribute to HIV-related CAD; 3) pursue basic research evaluating how ART may lead to direct and indirect toxic effects on the vascular endothelium; and 4) conduct imaging studies to better understand the pathogenesis of HIV-related CAD.
Prevention and treatment
The WG noted that there was an urgent need for evidence from randomized clinical trials to effectively prevent and treat HIV-related CAD (46–50). The WG recommended pursuing both pilot studies with CV surrogate endpoints to provide preliminary data on novel agents, and large-scale randomized trials with clinical outcome endpoints to evaluate evidence-based CAD therapy in the HIV population. The WG identified the following critical scientific priorities in the prevention and treatment of HIV-related CAD: 1) demonstrate the safety, efficacy, and effectiveness of evidence-based therapies for HIV-related CAD; 2) test novel clinical interventions to prevent and treat HIV-related CAD in the HIV population; and 3) conduct pilot studies in the HIV population addressing inflammation and other novel CV risk factors that could be further tested in a larger phase trial that would include both HIV and non-HIV populations. The WG recommended addressing the research gaps in the prevention and treatment of HIV-related CAD by: 1) including CV outcomes in trials testing interventions for HIV to understand the effects of HIV therapies on the development of CAD; 2) collaborating with HIV-related clinical trial networks and investigators early during protocol development to ensure that trials are adequately powered to detect a meaningful difference in CV outcomes; 3) increasing the enrollment of HIV patients into CV intervention trials, to better assess the safety of interventions when performing subgroup analyses; 4) incorporating HIV testing into screening and randomization procedures to ensure that patients with HIV are identified; and 5) leveraging existing CV and HIV databases to pursue outcomes research evaluating patterns of care in the prevention, diagnosis, and treatment of HIV-related CAD, post-event outcomes, and implementation of evidence-based care.
Research strategy themes
The WG strongly endorsed enhanced communication, collaboration, and teamwork among investigators from the HIV and HLB scientific communities, as well as among the NIH institutes and centers, to effectively address HIV-related HLB disease. Specific recommendations were as follows:
Communication; collaboration and teamwork; leveraging resources; and training
The WG urged engaging both CV and HIV professional societies to raise awareness in their scientific communities about this emerging field. The WG recommended expanding the involvement of CV investigators in current HIV research networks to broaden network expertise and promote multidisciplinary communication. The WG participants also suggested developing a centralized resource for the scientific community to access information about the NHLBI AIDS program and opportunities for research and funding. In addition, the WG advised the NHLBI to promote scientific partnerships by ensuring that any potential funding opportunities included multidisciplinary collaboration as part of the review criteria.
Another major research strategy theme was to leverage available NIH programs, including existing cohort studies, clinical trials, and biorepositories. The WG recommended enriching HIV cohorts with adjudicated CV endpoints and increasing the enrollment of HIV patients into CV studies.
The WG recognized that in order for the field to advance, there needed to be concerted efforts to develop a scientific community with expertise in both HIV and CV disease. The WG encouraged investing resources in training early stage investigators and developing funding opportunities that would encourage multidisciplinary mentorship and collaboration among the HIV and CV scientific communities. The WG suggested that early-stage HIV and CV investigators receive cross-disciplinary training to learn fundamental skills in both fields.
NHLBI aids program: evaluating performance
After receiving the WG recommendations, the NHLBI staff recognized the importance of developing a system to evaluate whether the AIDS program effectively stimulates high quality peer-reviewed research (51,52). The first step in this process was to collectively develop performance measures to gauge how well the AIDS portfolio was being stimulated. The performance measures included the number of new HIV-related HLB peer-reviewed applications and awards, and whether applications and awards addressed the identified scientific gaps. Other performance measures included the number of new investigators entering the field and whether the supported research led to publications, citations, or changes in clinical practice guidelines. The NHLBI AIDS team also determined that regular portfolio analyses and assessment of performance measures were essential to promote a continuous cycle of learning and improvement of the AIDS program. Regular systematic reviews would allow the NHLBI to refine approaches on how best to stimulate peer-reviewed HIV-related HLB research, identify future scientific priorities, and make evidence-based decisions about future research investments.
Conclusions and Discussion
The increased survival of patients with HIV has reshaped the urgent public health needs of this population and triggered new research questions and scientific priorities. The NHLBI has a unique opportunity and an important mandate to take a leadership role in responding to the evolving research demands of HIV-related HLB disease. The WG recommendations laid the foundation for the next phase of the NHLBI AIDS program by identifying the key scientific priorities and strategic gaps that needed to be addressed in order to effectively stimulate HIV-related HLB research. In response to the WG recommendations, the NHLBI has developed an NHLBI AIDS website, made public presentations at professional meetings, such as the American Heart Association and the Conference on Retroviruses and Opportunistic Infections, released broad-based, multidisciplinary basic science and clinical research funding opportunities in HIV-related HLB disease, funded studies in HIV patients that evaluate CV interventions being tested in non-HIV populations, and launched the largest HIV-related CV randomized clinical trial to date (53–60). These collaborative efforts and actions have resulted in growth in the NHLBI AIDS scientific portfolio—including an increase in the number of peer-reviewed HIV-related HLB applications and awards, and a rise in the number of investigators entering the field. Importantly, the NHLBI is funding multidisciplinary partnerships between HIV and HLB investigators and is partnering with other NIH institutes to support large HIV-related HLB scientific programs and clinical trials. Finally, the NHLBI is regularly reviewing and assessing its HIV-related HLB scientific portfolio to assess progress, cultivate new areas for research, and plan for the future.
The WG was a pivotal event in the launch of the next chapter of the NHLBI AIDS program. Guided by the WG recommendations, the NHLBI will continue its efforts to stimulate innovative research, develop multidisciplinary scientific partnerships, and support cutting edge discoveries in HIV-related HLB disease. In making these valuable research investments, the NHLBI looks forward to invaluable returns—improved survival and quality of life, not only for patients with HIV, but for all patients with HLB disease.
For expanded information about the NHLBI AIDS Cardiovascular Working Group, please see the online version of this article.
Dr. Hsue has received consulting fees from Gilead and Amgen. Dr. Ridker is listed as a coinventor on patents held by the Brigham and Women’s Hospital and licensed to Seimens and AstraZeneca relating to the use of inflammatory biomarkers in cardiovascular disease and diabetes. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acquired immunodeficiency syndrome
- antiretroviral therapy
- coronary artery disease
- human immunodeficiency virus
- heart, lung, and blood
- National Heart, Lung, and Blood Institute
- National Institutes of Health
- working group
- Received November 14, 2014.
- Accepted December 9, 2014.
- American College of Cardiology Foundation
- ↵Centers for Disease Control and Prevention. HIV/AIDS statistics overview. Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, Sexual Transmitted Diseases and Tuberculosis Prevention, Centers for Disease Control and Prevention. November 10, 2014. Available at: http://www.cdc.gov/hiv/statistics/basics/index.html. Accessed December 9, 2014.
- Antiretroviral Therapy Cohort Collaboration
- Redig A.J.,
- Berliner N.
- Althoff K.N.,
- McGinnis K.A.,
- Wyatt C.M.,
- et al.,
- for the Veterans Aging Cohort Study (VACS)
- Boccara F.,
- Lang S.,
- Meuleman C.,
- et al.
- Hemkens L.G.,
- Bucher H.C.
- Baker J.V.,
- Lundgren J.D.
- Panel of experts from the Metabolic Disorders Study Group (GEAM), National AIDS Plan (SPNS), AIDS Study Group (GeSIDA)
- Jallow A, Ljunggren G, Wandell P, et al. Prevalence, incidence, mortality and co-morbidities amongst human immunodeficiency virus (HIV) patients in Stockholm County, Sweden: the Greater Stockholm HIV Cohort study. AIDS Care 2014;Oct 3:1–8.
- ↵NHLBI AIDS Working Group: Advancing HIV/AIDS Research in Heart, Lung, and Blood Diseases. September 6-7, 2012. Available at: http://www.nhlbi.nih.gov/research/reports/2012-aids-working-group.htm. Accessed December 9, 2014.
- Currier J.S.,
- Lundgren J.D.,
- Carr A.,
- et al.
- Boccara F.
- Kaplan R.C.,
- Kingsley L.A.,
- Sharret A.R.,
- et al.
- Rotger M.,
- Glass T.R.,
- Junier T.,
- et al.,
- for the MAGNIFICENT Consortium, INSIGHT, Swiss HIV Cohort Study
- Hsue P.Y.,
- Deeks S.G.,
- Hunt P.W.
- Lo J.,
- Plutzky J.
- Stein J.H.,
- Currier J.S.,
- Hsue P.Y.
- Dube M.P.,
- Stein J.H.,
- Aberg J.A.,
- et al.,
- Adult AIDS Clinical Trials Group Cardiovascular Subcommittee, HIV Medical Association of the Infectious Disease Society of America
- Boccara F.,
- Teiger E.,
- Cohen A.,
- et al.
- Lauer M.S.
- Friedman M.
- ↵National Heart, Lung, and Blood Institute. NHLBI AIDS Program. Available at: https://www.nhlbi.nih.gov/research/funding/aids/. Accessed December 9, 2014.
- RFA-HL-14-024: Basic Research in the Pathogenesis of HIV-Related Heart, Lung, and Blood (HLB) Diseases in Adults and Children (R01). October 23, 2014. Available at: http://grants1.nih.gov/grants/guide/rfa-files/RFA-HL-14-024.html. Accessed December 9, 2014.
- RFA-HL-14-029: Basic Research in the Pathogenesis of HIV-Related Heart, Lung, and Blood (HLB) Diseases in Adults and Children (R21). October 23, 2013. Available at: http://grants1.nih.gov/grants/guide/rfa-files/RFA-HL-14-029.html. Accessed December 9, 2014.
- RFA-HL-14-023: Clinical Research in the Prevention, Diagnosis, and Treatment of HIV-Related Heart, Lung, and Blood (HLB) Diseases in Adults and Children (R01). October 24, 2013. Available at: http://grants1.nih.gov/grants/guide/rfa-files/RFA-HL-14-023.html. Accessed December 9, 2014.
- Grinspoon S, Douglas PS. Project information U01HL123336: REPRIEVE-Clinical Coordinating Center. 2014. NIH RePORTER. Available at: http://projectreporter.nih.gov/project_info_description.cfm?aid=8730843&icde=22778856&ddparam=&ddvalue=&ddsub=&cr=4&csb=default&cs=ASC. Accessed December 9, 2014.
- Hoffmann U, Ribaudo H. Project information U01HL123339: REPRIEVE-Data Coordinating Center. 2014. NIH RePORTER. Available at: http://projectreporter.nih.gov/project_info_description.cfm?aid=8730997&icde=22778930&ddparam=&ddvalue=&ddsub=&cr=4&csb=default&cs=ASC. Accessed December 9, 2014.